Treatment of heart failure

ABSTRACT

The invention relates to perhexiline, or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure, as well as to a method for treating heart failure, which comprises administering to an animal in need thereof an effective amount of perhexiline, or a pharmaceutically acceptable salt thereof, to treat said heart failure. The invention further relates to a treatment programme for treating heart failure, which involves the co-use or co-administration of perhexiline with one or more other compounds that are advantageous in treating heart failure or the symptoms thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/785,077, filed May 21, 2010, which is (1) a continuation-in-part ofInternational Application No. PCT/GB2008/003913, filed Nov. 24, 2008,which claims the benefit of GB Application No. 0723100.4, filed Nov. 23,2007, and the benefit of U.S. Application No. 60/990,933, filed Nov. 29,2007, and (2) a continuation of International Application No.PCT/GB2009/050539, filed May 20, 2009. The entire contents of each ofthe above-identified applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Significant advances in therapy for heart failure (HF) with impairedsystolic function have improved quality of life, and increased survival.However up to 50% of patients who have clinical evidence of HF are foundto have a relatively (or near) normal left ventricular ejection fraction(HF with normal left ventricular (LV) ejection fraction syndrome(HFnEF), also referred to as HF with preserved left ventricular ejectionfraction syndrome (HFpEF). Patients with HFnEF represent a rapidlyincreasing proportion of patients hospitalised and suffering mortalityfrom heart failure.

Despite a normal EF, HFnEF patients manifest subtle systolic dysfunctionbut the principal abnormality in most is a disorder of active relaxationand/or passive filling of the LV. However resting measures of activerelaxation and filling relate poorly to symptoms and exercise capacitytherefore no ‘gold standard’ diagnostic echocardiographic test existsfor HFnEF. Effective ventricular filling results from a highly energydependent active relaxation process and from passive filling which isdependent on loading conditions as well as the intrinsic (passive)properties of the LV. Since both these parameters change markedly duringexercise due to sympathetic activation, it is not surprising that theseresting parameters are so poorly predictive of exercise capacity andsymptoms.

The treatment of patients with HFnEF is discussed in Hunt et al.,“ACC/AHA 2005 Guideline Update for the Diagnosis and Management ofChronic Heart Failure in the Adult”, 2005, Section 4.3.2, available atwww.acc.org.

Perhexiline (2-(2,2-dicyclohexylethyl)piperidine) is a knownanti-anginal agent that operates principally by virtue of its ability toshift metabolism in the heart from free fatty acid metabolism toglucose, which is more energy efficient.

WO-A-2005/087233 discloses the use of perhexiline for the treatment ofchronic heart failure (CHF) where the CHF is a result of an initialinciting influence of ischaemia or where the CHF is a result of aninitial non-ischaemic inciting influence.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provideda method of treating HFnEF, which comprises administering to an animalin need thereof an effective amount of perhexiline, or apharmaceutically acceptable salt thereof, to treat said HFnEF. Theanimal is preferably a mammal and most preferably a human.

According to another aspect of the present invention, perhexiline, or apharmaceutically acceptable salt thereof, is provided for use in thetreatment of HFnEF.

According to a further aspect of the invention there is provided atreatment programme for treating HFnEF, which involves the co-use orco-administration of perhexiline or pharmaceutically acceptable saltthereof with one or more other compounds that are advantageous intreating HFnEF or the symptoms thereof, for example a diuretic, anangiotensin receptor blocker or a calcium channel blocker.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C displays variables correlating with Aerobic ExerciseCapacity (VO₂max) in HFnEF patients and controls.

FIGS. 2A and 2B show MR images of a patient with HFpEF lying prone overa ³¹P surface coil and FIG. 2C shows the corresponding localized ³¹P MRspectra from the left ventricle. FIG. 2D is Individual PCr/γ-ATP ratioin Patients with HFpEF and Controls.

FIG. 3 is a flow chart of a study carried out to establish a causativerole for energy deficiency and to evaluate the impact of perhexiline oncardiac energy status in HCM.

FIGS. 4A-4D represent the baseline data of HCM vs controls, moreparticularly:

FIG. 4A represents the peak oxygen consumption (peak VO₂max) results;

FIG. 4B represents the diastolic ventricular filling results (nTTPF,normalized for heart rate Time To Peak Filling) and shows that PCr/γATPratio (a measure of cardiac energetic state) is lower in HCM patientsversus controls;

FIG. 4C is an example of ³¹P cardiac spectra of a HCM patient in whichPoint C indicates centre of phosphorus coil, VOI; voxel of interest,2,3-DPG indicates 2,3-diphosphoglycerate; PDE, phosphodiesters; PCr,phosphocreatine; α, β, γ indicate the three phosphorus nuclei of ATP,and shows that nTTPF (a measure of the rate of active relaxation of theLV) is essentially unchanged on exercise in the controls bu abnormallyslows in the HCM patients; and

FIG. 4D represent the myocardial energetic results (PCr/γATP ratio) andshows that exercise capacity (peak VO₂) is lower in HCM patients versuscontrols.

FIGS. 5A and 5B respectively represent the effect of Placebo andPerhexiline on peak oxygen consumption (peak VO₂), p=0.003 andmyocardial energetic (PCr/γATP ratio), p=0.003, where the p valuerepresents the significant difference between perhexiline and placeboresponse. Peak VO₂ (exercise capacity) increases with Perhexiline (FIG.5A). Perhexiline improves PCr/γATP ratio (energetic status of heart),but this was unchanged in the placebo group (FIG. 5B).

FIGS. 5C and 5D respectively represent nTTPF changes in the placebogroup (3C) and the perhexiline group (3D), p=0.03, where the p valuerepresents the significant difference between perhexiline and placeboresponse. In the placebo group nTTPF (a measure of the rate of LV activerelaxation) abnormally lengthened at baseline and on treatment. Theresponse in healthy controls is shown in dotted lines. Perhexiline (FIG.5D) normalises the response to similar to that seen in healthy controls(also shown in dotted lines).

FIGS. 5E and 5F illustrate that NYHA score (of breathlessness) falls(improves) with perhexiline (5E) and Minnesota living with heart failurequestionnaire score falls (=improved quality of life) on perhexiline(5F).

FIG. 6 illustrate the causative role for energy deficiency in thepathophysiology of HCM.

DETAILED DESCRIPTION OF THE INVENTION

The findings of the study reported in Example 1 herein are that a) HFpEFpatients manifest a significant reduction in PCr/γATP ratio at rest,indicating impairment of myocardial energy ‘reserves’ and b) duringexercise, the energetically demanding active relaxation stage ofdiastole lengthened in patients (vs. a shortening in controls) and therewas also a failure of contractile function to increase in patients.These abnormalities together resulted in a lower stroke volume onexercise. It was also found that HFpEF patients demonstratedchronotropic incompetence on exercise.

These findings correlate closely with findings in a study of patientswith hypertrophic cardiomyopathy (HCM), which is reported in Example 2.The study of Example 2 also demonstrated the effectiveness of the agentperhexiline in the treatment of patients with HCM. Because of therelated pathophysiology of HFnEF and HCM, the inventors are able topredict, based on the effectiveness of perhexiline in the treatment ofHCM, that this same agent will be an effective therapeutic agent fortreatment of HFnEF.

In aspects of the present invention, the perhexiline exists in the formof a salt of perhexiline, preferably the maleate salt. The perhexilinemay be used at doses titrated to achieve therapeutic but non-toxicplasma perhexiline levels (Kennedy J A, Kiosoglous A J, Murphy G A,Pelle M A, Horowitz J D. “Effect of perhexiline and oxfenicine onmyocardial function and metabolism during low-flow ischemia/reperfusionin the isolated rat heart”, J Cardiovasc Pharmacol 2000; 36(6):794-801).Typical doses for a normal patient would be 100 mg to 300 mg daily,although smaller doses may be appropriate for patients who are slowmetabolisers of perhexiline.

Physiologically acceptable formulations, such as salts, of the compoundperhexiline, may be used in the invention. Additionally, a medicamentmay be formulated for administration in any convenient way and theinvention therefore also includes within its scope use of the medicamentin a conventional manner in a mixture with one or more physiologicallyacceptable carriers or excipients. Preferably, the carriers should be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Themedicament may be formulated for oral, buccal, parental, intravenous orrectal administration. Additionally, or alternatively, the medicamentmay be formulated in a more conventional form such as a tablet, capsule,syrup, elixir or any other known oral dosage form.

The invention is illustrated by the following non-limiting examples.

EXAMPLE 1

The role of exercise related changes was evaluated in left ventricular(LV) relaxation and of vasculo-ventricular coupling as the mechanism ofexercise limitation in patients with heart failure with normal (orpreserved) LV ejection fraction (HFnEF) and whether cardiac energeticimpairment may underlie these abnormalities.

The study involved 37 patients with HFpEF and 20 matched controls.Vasculo-ventricular coupling (VVC) and Time to Peak LV Filling (ameasure of LV active relaxation) (nTTPF) were assessed at rest and onexercise by Multiple Uptake Gated Acquisition scanning. Cardiacenergetic status (PCr/γATP ratio) was assessed by ³¹P Magnetic ResonanceSpectroscopy. At rest nTTPF and VVC were similar in patients andcontrols. Cardiac PCr/γATP ratio was reduced in patients vs. controls(1.57±0.52 vs. 2.14±0.62; P=0.003). VO₂max was lower in patients vs.controls (19±4 vs. 36±8 ml/kg/min; P<0.001). During maximal exercise theheart rate increased less in patients vs. controls (52±16 vs. 81±14 bpm;p<0.001) and the relative changes in stroke volume and cardiac outputduring submaximal exercise were lower in patients vs. controls(0.99±0.34 vs. 1.25±0.47, P=0.04; 1.36±0.45 vs. 2.13±0.72, P<0.001).nTTPF fell during exercise in controls, but increased in patients(−0.03±12 sec vs. +0.07±0.11; P=0.005). VVC decreased on exercise incontrols but was unchanged in patients (−0.01±0.15 vs. −0.25±0.19;p<0.001). Heart rate, VVC and nTTPF were independent predictors ofVO₂max.

Methods

Patients

The study involved 37 HFpEF patients prospectively recruited from heartfailure clinics. Also studied were twenty age-gender-matched healthycontrols with no cardiac history or diabetes mellitus. Studyparticipants had clinical examination, 12-lead electrocardiogram,pulmonary function test, echocardiogram, metabolic exercise test,radionuclide ventriculography and a subgroup underwent cardiac ³¹P MRSstudies to assess cardiac energetic status. All controls had a normalcardiovascular examination, 12-lead electrocardiogram andechocardiogram. HFpEF patients were defined in accordance with ACC/AHArecommendation (1): i) symptoms and signs of heart failure, ii) ejectionfraction ≧50%, iii) no valvular abnormalities. In addition it wasstipulated that patients should have iv) VO₂max <80% of age and genderpredicted with a pattern of gas exchange on metabolic exercise testingindicating a cardiac cause for limitation, v) absence of objectiveevidence of lung disease on formal lung function testing and/or absenceof arterial desaturation during exercise and with a ventilatory reserveat peak exercise ≧15 L. This definition was chosen in order to haverobust evidence that patients had exercise limitation that was cardiacrather than non cardiac in origin and so as not to prejudge theunderlying pathophysiology by stipulating the presence of restingdiastolic abnormalities because mild diastolic abnormlities arefrequently present also in healthy elderly subjects and moderate tosevere resting diastolic abnormalities are frequently not present inpatients with clear evidence of HFpEF. Patients with rhythm other thansinus were excluded.

Echocardiography

Echocardiography was performed with participants in the left lateraldecubitus position with a Vivid 7 echocardiographic machine using a2.5-MHz transducer. Cardiac quantifications were determined inaccordance with European Association of Echocardiography. (2) LVend-systolic elastance (Ees), a measure of LV contractility, wasdetermined using the non-invasive single-beat technique. (3) Arterialelastance (Ea), a measure of the stiffness of the entire arterial tree,was calculated as the ratio of LV end-systolic pressure/stroke volume.Studies were stored digitally and analyzed off-line.

³¹P Cardiac Magnetic Resonance Spectroscopy (MRS)

In vivo myocardial energetics was measured by MRS at 3-Tesla (4). ³¹Pcardiac magnetic resonance spectroscopy was performed using a PhillipsAchieva 3T scanner and a linearly polarized transmitter and receiver ³¹Pcoil with a diameter of 14 cm. The repetition time was 10000 ms with 136averages and 512 samples. Acquisition was ECG gated and the triggerdelay was set to acquire in diastole. Total scan time was 23 minutes(5). Java magnetic resonance user interface v3.0 (jMRUI) was used foranalysis. PCr and γ-ATP was used to determine the PCr/γATP ratio whichis a measure of cardiac energetic state (6). Patients with ischemicheart disease and diabetes (N=7) were excluded from the MRS studiesbecause these conditions are known to have impaired cardiac energetics(7,8). Patients with contraindications were also excluded from the MRSstudy (N=5). One patient's spectra was excluded from the analysis due topoor quality. Three controls had contraindication to MRS study. Datawere analysed separately by an investigator unaware of participants'clinical status.

Radionuclide Ventriculography

LV ejection fraction and diastolic filling were assessed by radionuclideventriculography at rest and during graded semi erect exercise on acycle ergometer as previously described. (9,10) Three minutes of datawere acquired at rest and during exercise after a 30-second period forstabilisation of heart rate at the commencement of each stage. Exercisewas performed at 50% workloads of heart rate reserve. Data were analysedusing LinkMedical MAPS software, Sun Microsystems (Hampshire, UK). Peakleft ventricular filling rate in terms of end-diastolic count per second(EDC/s) and time to peak filling normalised for R-R interval (nTTPF) inmilliseconds after end systole were calculated from the first derivativeof the diastolic activity-time curve. Venous blood samples were obtainedfor weighing and for counting of blood gamma activity during each scanin order to correct for physical and physiological decay as well as fordetermination of relative volume changes. (11) The validity of theseradionuclide measures of diastolic filling at high heart rates has beenestablished previously. (12)

All gated blood pool scan-derived volumes were normalized to bodysurface area, yielding their respective indexes: end-diastolic volumeindex (EDVI), end-systolic volume index (ESVI), stroke volume index(SVI), and cardiac index. The following indexes were calculated: a)arterial elastance index (EaI)=ESP/SVI; b) LV end-systolic elastanceindex (ELVI)=ESP/ESVI and c) vasculo-ventricular coupling ratio(VVC)=EaI/ELVI=(1/EF)−1. (13)

Metabolic Exercise Test

All participants underwent a symptom-limited erect treadmill exerciseusing a standard ramp protocol with simultaneous respiratory gasanalysis. (14)

Statistics

Continuous variables are expressed as means±SD. Unpaired Student'st-test (2-tail) was used to assess differences between mean values.Categorical variables were compared with Pearson Chi-Square test. Allreported P values were calculated on the basis of two sided tests and aP value of <0.05 was considered to indicate statistical significance.Variances of data sets were determined using F-test. Pearson correlationcoefficient (r) was used to describe the relationship between variables.All subjects were included into the model. Variables of interest thatwere found to correlate with the dependent variable on univariateanalysis were included in a stepwise linear regression analysis toidentify independent variables. SPSS (v15.0) was used to perform thestatistical operations.

Results

The results obtained are set forth in Tables 1-3 below and in FIGS.1A-1C and 2A-2D.

In FIGS. 1A-1C variables correlating with Aerobic Exercise Capacity(VO₂max) are shown. Panel A: VO₂max correlated negatively withExercise-induced Changes in nTTPF. Panel B: VO₂max correlated negativelywith Exercise-induced Changes in Vasculo-Ventricular Coupling Ratio.Panel C: VO₂max correlated directly with Exercise-induced Changes inHeart Rate. Black circles indicate patients with HFpEF, and Open circlesrepresents healthy controls. When patients on beta blockers wereexcluded from analysis, the level of significance were similar.

In FIG. 2, Panel A shows an MR images of a patient with HFpEF lyingprone over a ³¹P surface coil and the corresponding localized ³¹P MRspectra from the left ventricle is shown in panel B. The resonancesderive from PCr and the γ-, α-, and β-phosphate Resonances of the ATP.Panel C Individual PCr/γ-ATP ratio in Patients with HFpEF and Controls.The PCr/γ-ATP ratio was significantly reduced in patients with HFpEFcompared to healthy controls, P=0.003

TABLE 1 Baseline Characteristics of the Subjects Patient ControlVariable (N = 37) (N = 20) P Value Age - yr 67 ± 9  63 ± 7  0.51 Femalesex - no. (%) 28 (76) 10 (50) 0.05 Body Mass Index 30 ± 4  26 ± 5  <0.01Left Ventricular Hypertrophy - 19 (51)  5 (25) 0.05 no. (%) Diabetesmellitus - no. (%)  4 (11) 0 — Hypertension - no. (%) 27 (73) 0 —Ischemic Heart Disease - no. (%)  4 (11) 0 — NYHA functional class - no.I 10 0 — II 18 0 — III  8 0 — Drug therapy - no. (%) Diuretic 10 (27) 0— ACE inhibitor 20 (54) 0 — ARB  6 (16) 0 — Beta-blocker  8 (22) 0 —Calcium blocker 10 (27) 0 — Alpha Blocker  4 (11) 0 — Spironolactone 2(5) 0 — Nitrate 3 (8) 0 — VO₂max (ml/kg/min) 19 ± 4  36 ± 8  <0.001Respiratory Exchange Ratio (RER) 1.06 ± 0.07 1.13 ± 0.10 0.003 BreathingReserve - L/min 36 ± 15 43 ± 18 0.16 Exercise Time - min 6 ± 2 7 ± 10.03 Resting HR - beats/min 74 ± 14 83 ± 17 0.03 Peak HR - beats/min 127± 20  166 ± 11  <0.001 ΔHR - beats/min 52 ± 16 81 ± 14 <0.001 Rest SBP(mmHg) 138 ± 19  131 ± 23  0.23 Rest DBP (mmHg) 81 ± 11 81 ± 12 0.98Rest MABP (mmHg) 100 ± 12  96 ± 15 0.30 Peak SBP (mm/Hg) 182 ± 26  190 ±30  0.30 Peak DBP (mmHg) 81 ± 13 84 ± 10 0.36 Peak MABP (mmHg) 113 ± 17 114 ± 25  0.91 Left ventricular ejection 64 ± 14 63 ± 6  0.77 fraction -% Mitral E-wave velocity - m/sec 0.72 ± 0.19 0.61 ± 0.12 0.02 MitralA-wave velocity - m/sec 0.80 ± 0.20 0.59 ± 0.17 <0.001 Ratio ofE-wave:A-wave velocity 0.96 ± 0.35 1.03 ± 0.32 0.47 Mitral E-wavedeceleration - msec 274 ± 70  269 ± 73  0.82 E/E′ (septum) 15 ± 5  11 ±3  0.003 E/E′ (lateral) 12 ± 4  8 ± 2 <0.001 E_(es) 3.07 ± 1.07 2.60 ±.53  0.09 E_(a) 2.22 ± 0.63 2.28 ± 0.48 0.69

Plus-minus values are means±SD. When patients on beta blockers wereexcluded from analysis, the level of significance were similar apartfrom resting HR (P=0.14). NYHA denotes New York Heart Association, ACEangiotensin-converting enzyme, ARB angiotensin II receptor blockers, BMIbody mass index, SBP systolic blood pressure, DBP diastolic bloodpressure, MABP mean arterial blood pressure, LA left atrium, E/E′ mitralE-wave velocity-E′ tissue velocity (PW-TDI) at basal inferoseptum ratio,Ees denotes Left Ventricular End-Systolic Elastance and Ea is Arterialelastance. The bodymass index is the weight in kilograms divided by thesquare of the height in meters.

TABLE 2 MUGA at Rest and on Exercise: Diastolic Filling Characteristics,Systolic Function, Relaxation, Stiffness, and Ventricular-ArterialCoupling Patient Control Variable (N = 37) (N = 20) P Value Heart Rate -rest (beats/min) 71 ± 12 68 ± 15 0.40 Heart Rate - exercise 97 ± 14 114± 11  <0.001 (beats/min) Exercise SBP (mm/Hg) 204 ± 26  198 ± 27  0.45Exercise DBP (mmHg) 95 ± 15 97 ± 7  0.56 Exercise MABP (mmHg) 132 ± 15 131 ± 9  0.85 Ejection fraction - rest (%) 65 ± 9  64 ± 9  0.61 Ejectionfraction - 66 ± 9  72 ± 8  0.05 exercise (%) Peak emptying rates - rest382 ± 106 400 ± 90  0.56 (EDC/sec) Peak emptying rates - 477 ± 123 563 ±144 0.04 exercise (EDC/sec) Peak filling rates - 342 ± 120 321 ± 1110.54 rest (EDC/sec) Peak filling rates - exercise 504 ± 127 602 ± 1630.02 (EDC/sec) Time to peak filling - at 176 ± 80  181 ± 56  0.84 rest(msec) Time to peak filling - 246 ± 91  162 ± 80  0.001 exercise (msec)Relative Δ Stroke Volume 0.99 ± 0.34 1.25 ± 0.47 0.04 Index Relative ΔCardiac Output 1.36 ± 0.45 2.13 ± 0.72 <0.001 Index Relative Δ E_(LV)I -exercise 1.35 ± 0.50 1.85 ± 0.63 0.01 Relative Δ E_(a)I - exercise 1.52± 0.48 1.28 ± 0.44 0.17 Vasculo-Ventricular Coupling 0.57 ± 0.20 0.62 ±0.22 0.36 ratio (VVC) (E_(a)I/E_(LV)I) - rest Vasculo-VentricularCoupling 0.55 ± 0.19 0.41 ± 0.15 0.01 ratio (VVC) (E_(a)I/E_(LV)I) -exercise Δ VVC −0.01 ± 0.15  −0.25 ± 0.19  <0.001

Plus-minus values are means±SD. When patients on beta blockers wereexcluded from analysis, the level of significance were similar apartfrom peak filling rates during exercise (P=0.08). EDC end diastoliccount. SBP systolic blood pressure, DBP diastolic blood pressure, MABPmean arterial blood pressure. Relative Δ Stroke Volume Index is SViEXERCISE/SVi REST. Relative Δ Cardiac Output Index is COi EXERCISE/COiREST. Relative Δ ELVI is ELVIEXERCISE/ELVIREST. Relative Δ EaI isEaIEXERCISE/EaIREST. Δ Vasculoventricular coupling ratio is(EaI/ELVI)EXERCISE−(EaI/ELVI)REST. Δ VVC −0.01±0.15 −0.25±0.19 <0.001.

TABLE 3 Multivariate Predictors of VO₂ max Variable R Square P ValueExercise-induced change in HR* 0.584 <0.001 Exercise-induced change inVVC^(†) 0.696 0.003 Age^(‡) 0.728 0.018 Exercise-induced changenTTPF^(§) 0.769 0.018 *Predictors: ΔHR, ^(†)Predictors: ΔHR and Δ VVCcoupling ratio, ^(‡)Predictors: ΔHR, Δ VVC coupling ratio and age,^(§)Predictors: ΔHR, Δ VVC coupling ratio, age and ΔTTPF. Multivariateanalysis was adjusted for the variable that some patients were onbetablockers.Characteristics of the Patients

HFpEF Patients were generally females, overweight, aged 67±9 years oldwith a history of hypertension, however blood pressure was well treated(systolic BP 138±19 mmHg vs. 131±23 mmHg; p=0.23, in patients vs.controls) (see Table 4 below). The tissue Doppler E/E′ at the basalanterolateral left ventricular wall (a measure of left ventricularend-diastolic pressure) (15), was significantly higher in patients thancontrols. There was also a trend (non-significant) to higher Ees inpatients than in the control group. HFpEF patients also hadsignificantly reduced VO₂max and reduced peak HR on metabolic exercisetesting. There was a positive correlation between VO₂max and ΔHR(HREXERCISE−HRREST) (r=0.7, P<0.001) (see FIG. 1C). During semi-erectcycle exercise the relative stroke volume (SVi EXERCISE/SVi REST) waslower in patients compared to controls (0.99±0.34 vs. 1.25±0.47;P=0.04), and relative cardiac output (COiEXERCISE/COiREST) was alsolower (1.36±0.45 vs 2.13±0.72; p<0.001). (see Table 2)

Left Ventricular Active Relaxation nTTPF is determined by the rate ofactive relaxation (16) and by transmitral pressure gradient at the timeof mitral valve opening. nTTPF was similar at rest in HFpEF patients andcontrols. During exercise it shortened in controls, but lengthened inpatients (Table 2). There was a negative correlation between VO₂max andΔnTTPF (nTTPFEXERCISE−nTTPFREST) (r=−0.4, P=0.005) (see FIG. 1A).Furthermore, during exercise other radionuclide ventriculographydiastolic filling variables such as peak filling rates as well assystolic function parameters e.g. EF and peak emptying rates, weresignificantly reduced in patients compared to controls. (see Table 2)Left Ventricular Contractile Function and Vasculo-Ventricular Coupling

VVC was similar at rest in HFpEF patients and controls. During exercise,LV arterial elastance, a measure of the stiffness of the entire arterialtree, increased in both patients and controls but tended to increasemore in patients. LV end systolic elastance, a measure of LV contractilefunction, markedly increased on exercise in controls but increasedsubstantially less in patients. Accordingly the vasculoventricularcoupling ratio was essentially unchanged on exercise inpatients but fellsubstantially on exercise in healthy controls furthermore whilst restingLVEF and peak emptying rate were similar in patients and controls onexercise both were lower in patients. There was a negative correlationbetween VO₂max and Δ VVC on exercise (r=−0.6, P<0.001) (FIG. 1B).

In Vivo Myocardial Energetic State

At rest, cardiac PCr/γATP ratio in HFpEF patients (N=24) wassignificantly reduced compared to healthy controls (N=17), 1.57±0.52 and2.14±0.63, respectively, P=0.003 (see FIG. 2D).

Independent Predictors of Aerobic Exercise Capacity

In the multivariate analysis, a linear-regression model was used toexamine VO₂max as the dependent variable and found that exercise-inducedchanges in HR, VVC and nTTPF were independent predictors of VO₂max. (seeTable 3)

Discussion

The principal findings are: a) HFpEF patients manifest a significantreduction in PCr/γATP ratio at rest, indicating impairment of myocardialenergy “reserve” that is likely to be exacerbated during exercise. b) Asa corollary, during exercise, the energetically demanding activerelaxation stage of diastole lengthened in patients (vs. a shortening incontrols) and was accompanied with a failure to increase LV contractilefunction. These combined dynamic abnormalities of both diastolic andcontractile function together resulted in a lower stroke volume onexercise. c) Consistent with previous studies, HFpEF patientsdemonstrated chronotropic incompetence on exercise. (17). d) This studyunderlines the importance of dynamic (rather than resting) assessment ofcardiac function to comprehensively characterise patients with HFpEF.

The pathophysiology of HFpEF has been the subject of considerablecontroversy. These patients are typically hypertensive and exhibitimpaired LV active relaxation and/or increased passive left ventriculardiastolic stiffness at rest. (18) This has led many to conclude thatexercise limitation is primarily a result of impaired LV diastolicfilling and to the use of the term ‘diastolic heart failure’ by some.(19) However, diastolic dysfunction is also a common finding at rest inhealthy elderly subjects. (20) Furthermore, ‘subtle’ abnormalities ofsystolic function, in particular long axis systolic function, are alsoalmost universally observed in HFpEF patients despite normal LV ejectionfraction. (21) This has led others to propose that HFpEF ispredominantly a disorder of contractile function. (22) In order tocompare both of these possibilities, we defined HFpEF as a limitation ofexercise with an unequivocally cardiac cause as assessed by VO₂max(rather than using resting diastolic parameters) to avoid biasing ourmechanistic studies to a select group of patients with HFpEF.

Little attention has been directed to changes in systolic and diastolicfunction during dynamic exercise, which is when the majority of patientsexperience most severe symptoms. In one study, ten patients with HFpEFwere assessed with invasive pressure volume loops and compared withage-matched controls. (23) The former had increased arterial elastance(a measure of the stiffness of the entire arterial tree), and increasedLV end-systolic elastance (a measure of the stiffness of the ventricleduring systole, and the relatively load independent measure of thecontractile state of the left ventricle. (24) Whilst diastolicabnormalities were not universally present in patients at rest, markeddifferences appeared during handgrip exercise. The rate of LV activerelaxation increased in healthy subjects but it slowed in patients. (25)Another study from the same group, exercise-related symptoms inAfro-Caribbean hypertensive patients appeared to be strongly associatedwith chronotropic incompetence and an inadequate vasodilator reserve onexercise. (26)

The present study examined the patho-physiological mechanisms andpredictors of exercise limitation in a substantially larger series ofpatients during a much more physiologically relevant form of exercise(dynamic leg exercise). There were marked dynamic abnormalities in bothcontractile and diastolic function of the left ventricle, and a lowerpeak exercise HR in patients. The independent predictors of impairedexercise capacity were abnormal ventricular-arterial coupling onexercise, a reduced HR response on exercise and a ‘paradoxical’ slowingof the rate of LV active relaxation on exercise (manifest as aprolongation of nTTPF). Despite the relative robustness of theseobservations, deciding whether these changes are adaptive or maladaptiveremains challenging. The independent value of an impaired chronotropicresponse in predicting exercise capacity in HFpEF exemplifies thischallenge. For example, VO₂max is largely determined by cardiac outputon exercise and the latter is simply the product of HR and SV. On thisbasis, the detrimental consequecnes of an impaired HR appear plausible.However, in the setting of a profound slowing of active relaxation andincreased LV passive diastolic stiffness, a longer diastolic fillingperiod might be expected to be beneficial, both by increasing SV andreducing the cardiac energy load. This in part explains the efficacy ofβ blocker therapy in hypertrophic cardiomyopathy, a classic cause ofHFpEF. (27) The latter also seems plausible, since increasing heart rateby atrial pacing has been shown to reduce supine resting stroke volumeand cardiac output in patients with HFpEF. (28) Nevertheless, despite alonger diastolic filling time, the relative change in SV was lower inour patients during sub-maximal exercise. However, this failure toincrease cardiac workload through limiting HR may represent a strategyof energetic parsimony in a heart with limited energy reserves. Finally,an alternative explanation is that an inadequate chronotropic responseis simply a consequence and/or contributor to heart failure. (29) Suchincompetence is typically present in systolic heart failure and is inpart a manifestation of impaired vagal tone. (30) Clearly it will beimportant to undertake further studies to assess whether heart rateplays a causal role in exercise limitation in HFpEF, because if so thismay be amenable to rate responsive pacing.

The same challenges arise when interpreting the role of an impairment ofvasculo-ventricular coupling in HFpEF. The patients in this study had ahistory of hypertension but were well treated with antihypertensives (inmost cases including vasodilators) therefore resting blood pressure andarterial elastance were not significantly higher than in the controlgroup. Consistent with prior studies (31), at rest, LV end-systolicelastance (a measure of contractility or systolic stiffness) tended tobe higher in patients although this did not reach significance. Theincrease in arterial elastance during exercise tended to be greater inpatients vs. controls (presumably reflecting a greater increase in largeartery stiffness). However, whilst left ventricular end-systolicelastance almost doubled during exercise in controls, the increase wasonly 35% in patients; hence VVC reduced by 33% during exercise incontrols but was unchanged in patients. These findings indicate ablunting of the physiological increase in the contractile state of theleft ventricle on exercise. As with heart rate, these changes may beinterpreted to be either maladaptive or adaptive. A failure toadequately augment contractile function against a high “relative load”of disease and hence a failure to optimise cardiac energetic efficiencymight be considered contributory to HFpEF. On the other hand, a smallerincrement in LV end-systolic elastance will reduce the absolute increasein energy demand in an already energy constrained heart at the cost ofan impaired dynamic increase in cardiac output.

Integrating these observations, we speculate that dynamic energyimpairment may account for the slowing of LV active relaxation onexercise as well as the failure of LV contractile function to increase.To increase the generalisability of this hypothesis, we avoidedpositively biasing our study by excluding patients with establishedcauses of cardiac energy deficiency (ischemic heart disease anddiabetes) (32,33). Nevertheless, the PCr/γATP ratio was stillsubstantially reduced in HFpEF patients vs controls at rest. The lowerPCr/γATP ratio in patients indicates a reduction of high energyphosphates reserve at rest. (34,35) Although the time required foracquisition of Cardiac MRS signals precluded the measurement of highenergy phosphate status on exercise, it is likely that any basalenergetic impairment will be exacerbated dynamically. This exacerbationof dynamic energetic impairment would explain the prolongation of theenergy demanding active relaxation as manifest by nTTPF. Moreover, thelower hearts rates and lesser increases in LV end-systolic elastance mayrepresent strategies to limit dynamic cardiac energy demands. The causefor this resting energy deficit may relate to insulin resistance (36),to impaired mitochondrial function as a result of ageing (37), and toneuroendocrine activation and aberrant substrate metabolism. (38) Suchobservations provide a rationale to assess the therapeutic value of‘metabolic agents’ that increase cardiac energetic status by alteringcardiac substrate use (39). These agents have shown promise in patientswith systolic heart failure. (40)

Study Limitations

The radionuclide exercise protocol involved asking subjects to maintaina HR which was 50% of HR reserve above their resting HR. Since this HRreserve was calibrated to peak HR rate, the absolute workload inpatients was lower. To have compared patients at the same workload wouldbe inappropriate since this would represent a higher relative workloadin patients. Moreover, most changes in SV occur in the first part ofexercise with subsequent increases in cardiac output being principallydue to increases in HR. (41) A small proportion of patients were onβ-blockers which may have affected their cardiovascular response toexercise, however, when these patients were excluded from the analysisthe findings and the level of significance remained unchanged. Inaddition, some patients were on calcium blockers however these were allperipherally acting (dihydropyridines for hypertension) and thereforeare not expected to affect the myocardium. Ideally we would have likedto measure cardiac energetics during exercise however cardiac MRSstudies during exercise is currently quite challenging more so if wetried to replicate the same dynamic leg exercise in the confinement of aMR scanner. MRS and Radionuclide studies also require a regular rhythm,thus patients with atrial fibrillation were excluded from the study. Incontrast, the strength of radionuclide studies is their increasingtemporal resolution at higher heart rates. This obviates the confoundingE:A fusion as is frequently experienced with exercise echocardiography.Radionuclide studies are thus not subject to systematically biasingmechanistic HFpEF towards a subgroup of patients without E:A fusion.

Conclusion

HFpEF patients have abnormal resting cardiac energetic status which whenexacerbated dynamically may contribute to the abnormal active relaxationon exercise and to a failure to increase LV end-systolic elastance. Inaddition chronotropic response was markedly impaired on exercise inpatients. The independent predictors of exercise capacity in patientswith HFpEF are exercise-induced changes in active relaxation, heart rateand ventricular-arterial coupling.

EXAMPLE 2

A study was carried out to establish a causative role for energydeficiency and to evaluate the impact of perhexiline on cardiac energystatus in HCM.

The study was approved by the South Birmingham Research Ethics Committeeand the investigation conforms with the principles outlined in theDeclaration of Helsinki. All study participants provided writteninformed consent. The study was a randomized, double blind,placebo-controlled parallel-group design of minimum 3 months duration.FIG. 3 represents a flow chart of the study. The pre-defined primary endpoint was peak oxygen consumption (peak VO2). Pre-defined secondary endpoints were symptomatic status, resting myocardial energetics (PCr/γ-ATPratio) and diastolic function at rest and during exercise (nTTPF). 33controls of similar age and gender distribution were recruited forcomparison with baseline data of HCM patients. All controls had nohistory or symptoms of any cardiovascular disease with normal ECG andechocardiogram (LVEF≧55%).

Patients were recruited from dedicated cardiomyopathy clinics at TheHeart Hospital, University College London Hospitals, London and QueenElizabeth Hospital, Birmingham, UK between 2006 and 2008. Inclusioncriteria were 18 to 80 years old symptomatic HCM patients (predominantsymptom breathlessness) in sinus rhythm with reduced peak VO2 (<75% ofpredicted for age and gender) and no significant LVOT obstruction atrest (gradient<30 mmHg). Exclusion criteria were presence of epicardialcoronary artery disease, abnormal liver function test, concomitant useof amiodarone or selective serotonin reuptake inhibitors (due topotential drug interactions with perhexiline), peripheral neuropathy andwomen of childbearing potential. Diabetic patients were also excluded tomaintain the blindness of the study as Perhexiline may lead to areduction in plasma glucose in such patients necessitating a reductionin anti-diabetic therapy. 46 consecutive consenting patients who metthese entry criteria were recruited into the study.

Patients were subjected to a number of tests and assessments as follows.

Cardiopulmonary Exercise Test

This was performed using a Schiller CS-200 Ergo-Spiro exercise machinewhich was calibrated before every study. Subjects underwent spirometryand this was followed by symptom-limited erect treadmill exercisetesting using a standard ramp protocol with simultaneous respiratory gasanalysis (Bruce R A, McDonough J R. Stress testing in screening forcardiovascular disease. Bull N Y Acad Med 1969; 45(12):1288-1305.;Davies N J, Denison D M. The measurement of metabolic gas exchange andminute volume by mass spectrometry alone. Respir Physiol 1979;36(2):261-267). Peak oxygen consumption (peak VO2) was defined as thehighest VO2 achieved during exercise and was expressed in ml/min/kg.

Symptomatic Status Assessment

All HCM patients filled in Minnesota Living with heart failurequestionnaire and were also assessed for NHYA class.

Transthoracic Echocardiography

Echocardiography was performed with participants in the left lateraldecubitus position with a Vivid 7 echocardiographic machine (GEHealthcare) and a 2.5-MHz transducer. Resting scans were acquired instandard apical 4-chamber and apical 2-chamber. LV volumes were obtainedby biplane echocardiography, and LVEF was derived from a modifiedSimpson's formula (Lang R M, Bierig M, Devereux R B et al.Recommendations for chamber quantification: a report from the AmericanSociety of Echocardiography's Guidelines and Standards Committee and theChamber Quantification Writing Group, developed in conjunction with theEuropean Association of Echocardiography, a branch of the EuropeanSociety of Cardiology. J Am Soc Echocardiogr 2005; 18(12):1440-1463.)Pulse wave doppler sample volume was used to assess resting LVOTOgradient.

Radionuclide Ventriculography

Diastolic filling were assessed by equilibrium R-wave gated blood poolscintigraphy using a standard technique at rest and during graded semierect exercise on a cycle ergometer (Atherton J J, Moore T D, Lele S Set al. Diastolic ventricular interaction in chronic heart failure.Lancet 1997; 349 (9067):1720-1724; Lele S S, Macfarlane D, Morrison S,Thomson H, Khafagi F, Frenneaux M. Determinants of exercise capacity inpatients with coronary artery disease and mild to moderate systolicdysfunction. Role of heart rate and diastolic filling abnormalities. EurHeart J 1996; 17(2):204-212). Peak left ventricular filling rate interms of end-diastolic count per second (EDC/s) and time to peak fillingnormalised for R-R interval (nTTPF) in milliseconds were measured atrest and during exercise (50% of heart rate reserve). The validity ofthese radionuclide measures of diastolic filling at high heart rates hasbeen established previously (Atherton et al. and Lele et al., seeabove).

31P Cardiac Magnetic Resonance Spectroscopy (MRS)

In vivo myocardial energetics were measured using a MRS at 3-TeslaPhillips Achieva 3T scanner (Shivu G N, Abozguia K, Phan T T, Ahmed I,Henning A, Frenneaux M. (31)P magnetic resonance spectroscopy to measurein vivo cardiac energetics in normal myocardium and hypertrophiccardiomyopathy: Experiences at 3T. Eur J Radiol 2008). A java magneticresonance user interface v3.0 (jMRUI) was used for analysis (see NaressiA, Couturier C, Castang I, de Beer R, Graveron-Demilly D. Java-basedgraphical user interface for MRUI, a software package for quantitationof in vivo/medical magnetic resonance spectroscopy signals. Comput BiolMed 2001; 31(4):269-286)). PCr and γ-ATP peaks was used to determine thePCr/γ-ATP ratio which is a measure of the cardiac energetic state(Neubauer S, Krahe T, Schindler R et al. 31P magnetic resonancespectroscopy in dilated cardiomyopathy and coronary artery disease.Altered cardiac high-energy phosphate metabolism in heart failure.Circulation 1992; 86(6):1810-1818). Data were analyzed by aninvestigator who was blinded to the participants' clinical status.Carmeo-Rao ratio was used to assess signal to noise ratio. A typicalexample of cardiac 31P MRS spectra from a patient with HCM is shown inFIG. 4C.

Intervention

Following baseline studies, patients were randomized in a double-blindfashion to receive either perhexiline (n=25) or placebo (n=21) 100 mgOD. Serum perhexiline levels were obtained at 1 and 4 weeks afterinitiation of the drug. Dose adjustments were advised by an unblindedphysician according to serum level to achieve therapeutic level and toavoid drug toxicity. Identical dosage adjustments were also made forrandomly allocated placebo-treated patients by the unblinded observer toensure that blinding of the investigators was maintained. At the end ofstudy, patients were re-evaluated as described earlier.

Statistical Analysis

Data were analyzed using SPSS ver. 15.0 for Window and Microsoft OfficeExcel 2007, and expressed as Mean±Standard Deviation (SD). Comparison ofcontinuous variables between Perhexiline and Placebo baseline data weredetermined by unpaired Student's t-test (2-tail) if variables werenormally distributed and the Mann-Whitney U-test if the data werenon-normally distributed. ANCOVA with baseline values as covariates wasperformed to test for the significance of differences in the perhexilineversus placebo group after treatment. For the primary end point, thesample size required to detect a change in peak Vo2 of 3 ml/kg/minversus placebo group with a power of 90% and probability of 5% is 44. 30patients will be required to identify a 5 change in cardiac PCr/γATPratio with a power of 90% and a p value of <0.05. 40 patients will berequired to detect a change ≧25% in nTTPF with power of 0.99 withprobability of 5%. Therefore, we aimed to study 50 patients includingthe drop-outs, 32 of them will take part in the MRS study.

The characteristics and treatment of participants are shown in Table 4below. Vo₂: refers to peak oxygen consumption, ACE: refers toangiotensin-converting enzyme, and ARB refers to angiotensin II receptorblockers.

TABLE 4 The clinical characteristics of HCM patients and controls. HCMHCM HCM Controls P value (Perhexiline) (Placebo) P value Age [years] 55± 0.26 52 ± 0.46 0.2 56 ± 0.46 54 ± 0.64 0.42 Number (Male) 46 (34) 33(20) 0.64 25 (19) 21 (17) 0.69 Heart Rate 69 ± 0.27 82 ± 0.47 <0.001* 69± 0.53 69 ± 0.52 0.97 [bpm] Systolic BP 126 ± 0.64  126 ± 0.44  0.93 123± 0.84  130 ± 0.92  0.2 [mm Hg] Diastolic BP 76 ± 0.25 78 ± 0.34 0.33 74± 0.45 78 ± 0.57 0.24 [mm Hg] Peak Vo₂ 23 ± 0.12 38 ± 0.24 <0.0001* 22.2± 0.2   23.56 ± 0.27   0.42 [ml/kg/min] Resting nTTPF 0.17 ± 0.002  0.18± 0.003  0.44 0.19 ± 0.003  0.17 ± 0.004  0.52 (sec) PCr/γATP ratio 1.28± 0.01   2.26 ± 0.02  <0.0001* 1.27 ± 0.02   1.29 ± 0.01  0.86 Drugtherapy - no. Beta- 17 0 — 10 7 0.21 blocker CC-blocker 24 0 — 11 8 0.53Diuretic 10 0 — 4 5 0.49 ACE 6 0 — 3 2 0.84 inhibitor ARB 4 0 — 3 1 0.41Warfarin 5 0 — 2 3 0.48 Statin 15 0 — 7 7 0.9 *indicates statisticalsignificance

Baseline Data (HCM Versus Controls)

The clinical characteristics and cardiopulmonary exercise test resultsof all the HCM patients and controls are shown in Table 4. The groupswere well matched with respect to age and gender. Heart rate was lowerin the HCM group compared to controls due to medication use (betablockers and/or calcium channel blockers).

The resting cardiac PCr/γATP ratio was lower in HCM patients than incontrols (1.28±0.01 vs 2.26±0.02, p<0.0001) (see FIGS. 4A and B), andthis remained so after excluding patients taking beta blocker therapy(p<0.0001). At rest, nTTPF, a sensitive marker of LV relaxation, wassimilar in HCM patients and controls (0.17±0.002 vs 0.18±0.003 sec,p=0.44). During submaximal exercise (at a workload that achieved 50% ofheart rate reserve) it remained relatively constant in controls (from0.18±0.003 sec to 0.16±0.002 sec, [nTTPF=−0.02±0.003 sec]), butlengthened in patients (from 0.17±0.002 to 0.34±0.002 sec,[nTTPF=+0.17±0.002 sec]) p<0.0001, (FIG. 4C). This pattern persistedafter exclusion of patients on beta blockers and remained significantlydifferent from controls (p<0.0001). Patients exhibited marked exerciselimitation compared to controls (23±0.12 vs 38±0.24 ml/kg/min, p<0.0001)(FIG. 4D).

Randomized, Double Blinded, Placebo-Controlled Parallel-Group

The perhexiline and placebo groups were well matched (see Table 4). Onlyone patient (on placebo) did not complete the study due to poorcompliance. Side effects were restricted to transient nausea (n=3) anddizziness (n=2) in the perhexiline group and transient nausea (n=2) andheadache (n=1) in the placebo group during the first week of treatment.There were no deaths during the study period.

Myocardial Energetics

The PCr/γATP ratio increased with perhexiline (1.27±0.02 to 1.73±0.02)as compared with placebo (1.29±0.01 to 1.23±0.01), p=0.003 (see FIG.5A). The mean Cramer-Rao ratios for PCr and γATP were 7.5% and 10.8%respectively. The effect of perhexiline on PCr/γATP ratio remainedsignificant after inclusion of the 3 patients with Cramer Rao ratios >20from the analysis (p=0.02).

Diastolic Ventricular Filling

Whereas the placebo group showed similar prolongation of nTTPF duringexercise before and after therapy (0.17±0.004 to 0.35±0.005 [nTTPF0.18±0.006 sec] and 0.23±0.006 to 0.35±0.005 sec [nTTPF 0.12±0.006 sec],respectively), in the perhexiline group there was a substantialimprovement on therapy with nTTPF at rest and exercise similar(0.19±0.003 to 0.19±0.004 sec [nTTPF 0.00±0.003 sec]) p=0.03 between theperhexiline and placebo response (see FIGS. 5B and 5C).

Symptomatic Status

More patients in the perhexiline group than in the placebo group hadimprovements in NYHA classification (67 percent vs. 30 percent) andfewer had worsening (8 percent vs. 20 percent) (p<0.001). MinnesotaLiving with heart failure questionnaire score showed an improvement(fall in score) in the perhexiline group (from 36.13±0.94 to 28±0.75)but did not change in the placebo group (p<0.001) (see FIGS. 5D and 5E).

Exercise Capacity (Peak Oxygen Consumption)

Peak V_(O2) at baseline was similar in the perhexiline and placebogroups (Table 4). After treatment, Peak V_(O2) fell by −1.23 ml/kg/minin the placebo group (from 23.56±0.27 to 22.32±0.27 ml/kg/min) butincreased by 2.09 ml/kg/min in the perhexiline group (from 22.2±0.2 to24.29±0.2 ml/kg/min), p=0.003 (see FIG. 5F).

Discussion of Results

The study indicates that patients with symptomatic HCM manifest acardiac energy defect at rest (reduced PCr/γATP ratio). This defect wasaccompanied by a slowing of the energy-requiring early diastolic LVactive relaxation during exercise (prolongation of nTTPF). The metabolicmodulator perhexiline resulted in significant myocardial energyaugmentation. Supporting a causative role for energy deficiency in thepathophysiology of HCM, this energy augmentation was accompanied bystriking normalisation of HCM's characteristic “paradoxical”nTTPF-prolongation in exercise. These biochemical and physiologicalimprovements translated into significant subjective (NYHA classificationand QoL score) and objective (V_(O2)) clinical benefits in symptomaticHCM patients already on optimal medical therapy (see FIG. 6).

The content of all cited references is expressly incorporated herein byreference for all purposes.

References

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What is claimed is:
 1. A method for treating heart failure in a mammalhaving a left ventricular ejection fraction of at least 50%, said methodcomprising administering to said mammal an effective amount ofperhexiline, or a pharmaceutically acceptable salt thereof, wherein saidmammal has diminished exercise capacity or tolerance.
 2. The method ofclaim 1, wherein said mammal has a diminished peak oxygen consumption(VO_(2max)) during exercise (Aerobic Exercise Capacity) and wherein theeffective amount of perhexiline, or a pharmaceutically acceptable saltthereof, is sufficient to increase the peak oxygen consumption(VO_(2max)) during exercise (Aerobic Exercise Capacity) in the mammal.3. The method of claim 1, wherein the mammal has no significant leftventricular outflow tract obstruction at rest (gradient <30 mmHg). 4.The method of claim 1, wherein the perhexiline is in the form of apharmaceutically acceptable salt.
 5. The method of claim 4, wherein theperhexiline is in the form of a maleate salt.
 6. The method of claim 1,wherein the mammal is a human.
 7. The method of claim 1, furthercomprising co-administering to said mammal at least one additionaltherapeutic compound.
 8. The method of claim 7, wherein the at least oneadditional therapeutic compound is selected from a member of the groupconsisting of Alpha Blockers, Beta Blockers, Calcium Channel Blockers,Diuretics, Ace (Angiotensin-Converting Enzyme) Inhibitors, Arb(Angiotensin II Receptor Blockers), Spironolactone, Nitrate, Warfarin,Verapamil, Insulin, Amiodarone, Lisinopril, Ramipril, Perindopril,Enalapril, Trandolapril, At2 Receptor Blockers, Losartan, Valsartan,Irbersartan, Carvedilol, Bisoprolol, Metoprolol, Atenolol, Aspirin,Clopidogrel, Oral Hypoglycaemics, Disopyramide, and Statins.
 9. Themethod of claim 1, wherein the mammal is further diagnosed as having amember of the group consisting of dyspnea (shortness of breath), chestpain, fatigue, palpitation and syncope.
 10. The method of claim 1,wherein the mammal is further diagnosed as having a reduced E:EA ratio,abnormally rapid skeletal muscle phosphocreatine depletion with delayedrecovery, reduced systolic velocity (PSV), or no significant leftventricular outflow tract obstruction at rest (gradient <30 mmHg). 11.The method of claim 1, wherein perhexiline is administered in an amountof 300 mg per day or less.
 12. The method of claim 1, whereinperhexiline is administered in an amount of 100 mg per day or less. 13.The method of claim 1, wherein perhexiline is administered in an amountof 100 mg to 300 mg per day.